Genetic variants and clinical factors affecting the response to 5-fluorouracil–based treatment in Chilean patients with advanced colorectal cancer.

Abstract

114 Background: Colorectal cancer (CRC) ranks as the second most common cancer in Chile, affecting both men and women. Late diagnosis results in approximately 25% of patients presenting with metastatic disease, with a five-year survival rate of about 14%. Standard treatment includes tumor resection followed by adjuvant chemotherapy, commonly involving 5-fluorouracil (5-FU) combined with drugs like oxaliplatin or irinotecan. However, patient responses to 5-FU vary greatly due to genetic polymorphisms in enzymes like thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPD), which affect the drug's pharmacokinetics and pharmacodynamics. Polymorphisms in genes related to oxaliplatin elimination and efficacy, such as glutathione-S-transferases (GSTs) and DNA repair enzymes, also play a role. However, the relationship between genetic variants and treatment outcomes remains unclear, often varying by population and cancer stage. Although predictive models for treatment response and risk exist for various diseases, no comprehensive model combining genetic and clinical variables to predict chemotherapy safety in Chilean CRC patients has been developed. Objective: This study aimed to identify relevant genetic variants in the genes TYMS , TYMP , DPYD , GSTP1 , MTHFR , ERCC2 , ABCB1 , ABCC2 , ABCC4 , and ABCG2 , which, along with clinical variables, could help create a predictive model for the safety of 5-FU-based chemotherapy in advanced CRC patients. Methods: A retrospective nested case-control study was conducted on 82 advanced CRC patients. Sixteen genetic variants were analyzed to assess their influence on adverse reactions (ADRs) and their severity, using logistic regression to identify potential associations. Multivariate models were developed to predict chemotherapy safety. Results: Among the 16 variants analyzed in 82 patients, several key findings emerged: The G allele of GSTP1 (rs1695) was found to be protective against neuropathy (OR = 0.147; p = 0.012) but increased the risk of mucositis (OR = 2.27; p = 0.036). The C allele of DPYD (rs1801265) was associated with an elevated risk of neuropathy (OR = 4.50; p = 0.05). The TYMS deletion (rs151264360) provided protection against cutaneous (OR = 0.029; p < 0.0001) and hematological ADRs (OR = 0.098; p = 0.005). Additionally, TYMS deletion was protective against severe toxic ADRs (OR = 0.098; p = 0.005). Two multivariate models were created to predict anemia (p = 0.027) and pain (p = 0.01) development. Conclusions: This study represents an initial step toward developing predictive models for ADRs related to 5-FU, such as neuropathy, mucositis, and hematological and skin toxicities. In the future, these findings may contribute to pharmacogenetic-based dose adjustment models aimed at reducing ADRs in Chilean CRC patients undergoing 5-FU-based treatment.